Every human being would like to
have an everlasting healthy life untouched by disease, and ageing process. The
starfish’s ability to regenerate its lost arms or the ability of the lizard to
regenerate its tail has fascinated both young minds and the wise alike. ‘What
if we have an option of replacing a malfunctioning organ with a brand new one’?
With Successful heart, kidney, liver, corneal transplantation, mankind today
has made a beginning in this direction. But,
these spares from other fellow beings come with limitations. The availability
of suitable donors, both the one who is willing to donate and importantly if
not more is the necessity of ‘cross match’ between the host and the donor. Thus,
shortage of organs and organ rejections are serious limitations. The possibility
of making our own organs soon received attention. Science of regenerative
medicine is an emerging interdisciplinary area that involves designing
customized organs and tissues using one’s own cells (the recipient in this case
is the donor himself/herself). It also encompasses the repair of tissues or
organs that are damaged in-situ and more recently also is expanded to include
the scope of improved function of an organ/ tissue. The key to progress in this
direction comes from a combination of the use of cells, materials, engineering
and creation of the milieu. Today, the term ‘stem cells’ which was initially proposed for scientific
use by Alexander Maksimov, a Russian histologist at
the congress of hematological society in Berlin, is a very popular one and
attracts significant interests both among the scientific community as well as
the general public. There are companies that offer their technology to preserve
stem cells for a future application. This might appear at least to some as a
more refined way (modern) of the ancient Egyptian quest for eternity. Perhaps
this is a field that did not have to take much effort to reach to public, in
most cases there was considerable attention even from media which may be quoted
as a good example of how research should translate to application, but
unfortunately it has led to some ‘unrealistic expectations’ as well.
Stem cells may be understood as a
mother cell that have the potential or ability to multiply and differentiate
into a more specialized cell or simply
can self renew to produce more stem cells. The well orchestrated and precise
transformation of a single cell (zygote) to a multicellular organism has been
the initial fuel for scientists working on the possibility of regenerative
medicine. The discovery of mouse embryonic stem cells by Martin Evans 1 for which he was
awarded a Nobel Prize in 2007 is notable. The concept of stem cells and
regeneration was contemplated as very little and or even absent in adults in
several instances. The present understanding seems to have favored the term ‘limited’
or ‘restricted’ ability rather than a blanket absence of ability. It was this
belief that probably was one of the inspirations to classify stem cells as
embryonic and adult stem cells. The functional distinction given to both these
types in an oversimplified language may be put this way. The embryonic stem
cell is a less differentiated cell which has a potential for rapid
proliferation and differentiation into many cell/ tissue types while the adult
stem cells have limited capacity. The obvious advantages of using embryonic
stem cells also come with some hiccups. They are feared to produce cancer as
well. Cancer Stem cells are believed to be an underlying cause for radio and
chemoresitance and even invasive properties of several known cancers. Therefore,
the current focus in regenerative medicine is with the use of adult stem cells.
Adult stem cells may again be for convenience classed as tissue resident (usually
unipotent cells, i.e. principally forms cells of that particular organ in which
they reside) and more centralized – multipotent (generalized cells, which may
differentiate to a number of cell/tissue types). The stem cells in the brain
(neural progenitor cells) located at the dentate gyrus and the sub ventricular
zone is an example of a resident stem cell while the stem cells in the bone
marrow may be considered as a more generalized cell. To put it simple an organ
specific stem cell help regenerate that organ while the other type may help
regenerate more than an organ. However this may not a very strict rule for
example some studies point to that the stem cells in the liver may act like
pancreatic stem cells when the pancreatic function is affected.
Can we create a stem cell? A
curious question, for which we already have some clues, cells have been
reprogrammed (de-differentiated?) to make them have stem cell like properties. John
Gurdon showed that a nucleus of an adult cell can be reprogrammed when placed
in an enucleated egg cell (somatic cell nuclear transfer). The resultant cell
can initiate normal development. This knowledge was put to practice
(surprisingly very soon) by Ian Wilmut and Campbell 2 which resulted in
Dolly, the first cloned sheep. Critics may buff this as a very complicated
process as if an answer came another astonishing finding in which Kazutoshi
Takahashi and Shinya Yamanaka3, 4
in 2006 demonstrated that reprogramming an adult cell is possible by addition of
just four transcription factors. These findings however again had the shadow as
viral vectors were used for inserting these transcriptional factors. Ever since
there has been a flood of activity in this area. Several research groups have
demonstrated in a span of just a few months non viral methods of transfer of
these factors. The reprogramming of a hepatocyte, B lymphocyte, pancreatic
islet beta cells soon followed. The generation of induced pluripotent cells
from patients with diseases like amyotrophic lateral sclerosis, adenosine
deaminase deficiency-related SCID, Parkinson’s disease and Down’s syndrome are
important milestones the field of regenerative medicine has passed.
Stem cells, Regenerative medicine
and tissue engineering.
The possibility of a complex
organ synthesized or rebuilt has been a major challenge. Perhaps the greatest
challenge being the milieu and the three dimensional spatial arrangements of
different cell types is the most crucial step towards this direction. Scaffolds
for supporting the spatial arrangement of the cells have been evolving. With rapid strides in the field of
biomaterials, especially biodegradable, self assembly polymers, nano materials
and the advancements in technologies like electrospinning, molecular self
assembly and phase separation used for generation of the modern day
biodegradable scaffolds have made the possibilities of synthetic organs stronger
today. Three different strategies have been applied for regenerative medicine.
1. Replacing the damaged tissue by injecting cells
suspensions or aggregates
2. The transplantation of bioartificial organs
synthesized outside the body.
3. In-situ regeneration
The proof of concept of their
differentiation ability of a stem cell to a particular lineage has been
demonstrated by laboratories across the globe. Dopaminergic neurons,
oligodentrocyte progenitor cells, motor neurons, pancreatic beta cells,
hepatocytes, Retinal cells are some of the examples of specific cell types
being produced from embryonic stem cells. However the safety issue especially
the risk of teratoma formation and the degrees of functional integration into
the tissues are concerns which are not adequately addressed. Induced
pluripotent stem cells offer a distinct advantage by virtue of their ability to
produce patient specific stem cells. Moreover a variety of adult cells have
been reprogrammed to make them multi or pluripotent. Skin fibroblasts,
kerationcytes, B lymphocytes, pancreatic beta cells, hepatocytes are a few
examples for cell types which has been reprogrammed.
Some of the most important and
probable applications may be in the field of chronic diseases, or even to
prevent aging or who knows even for eternity!
The practice of stem cells and regenerative medicine
Though the discovery of stem
cells date back to Raman V cajol, it use in scientific acceptance came much
more recently. The development in the 90’s and the burgeoning of regenerative
medicine, a multidisciplinary field is a more recent one. Hyderabad holds the privilege of of having
L.V. Prasad eye institute which perhaps are the world leaders in ‘successful
adult stem cell therapy’ for corneal replacement. One of the most accepted
procedure is bone marrow transplant. It is widely and effectively used world
over. Tissue engineered skin which was approved for clinical use from 1998 by
US FDA is in use ever since. Trans tissue migration, vascular and non vascular
migration of stem or progenitor cells which are more recently described
provides a boost to the regenerative process. Bone marrow
derived mesenchymal cells have found significant application in human regenerative
medicine, for treatment of many maladies like cardiac ischemia, cerebral
ischemia, chronic limb ischemia, foot ulcers, chronic knee arthritis. Several
diseases like Alzheimer’s, Parkinsonism, muscular dystrophies, refractory
systemic lupus erythematosus are possibly other important diseases in which
stem cells and regenerative medicine is expected to play a role.
Stem cells ethical, social and political debates
Does the story of Hela repeat? What
if we are able to make a whole human being, is there a possibility of making
the human war machines which many of the previous era dictators had dreamt of?
The use of embryonic stem cells raised many an eye brows, even the political
administrations of some of the most modern countries are having a tough time. Manipulation
of embryos, taking of cells has its own social, religious and political
implications.
As a general consensus today
organ or tissue regeneration are acceptable but not a whole human! However the
use of embryonic cells may not be acceptable for many.
As an alternate adult stem cells
and induced pluripotent cells are being tipped as the futures for regenerative
medicine. Perhaps as per the present understandings, Adult stem cells may be
best used for in situ regeneration
(repair, regeneration and even improving function of partly damaged organs or
tissues) and induced pluripotent cells could serve in organ or tissue
engineering where a whole organ or tissue is synthesized outside the host body.
Perhaps the greatest challenge
stem cell and regenerative medicine faces is stem cell mobilization,
recruitment, finally creation of the microenvironment and functional
integration.
To summarize, adult stem cells
are used in a number of therapies in humans but are yet not fully defined and
its availability is also limited. Embryonic stem cells can be differentiated
into almost all adult tissue types but carries the risk of cancer and are not
well in control. Significant efforts are being made to produce patient specific
stem cells by different techniques. This reprogramming of cells seems to hold
some promise for regenerative medicine but we are well behind in understanding
them.
References
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